3D-printed medicines, developed through the layer-by-layer addition of material, are becoming increasingly attractive alternatives to conventionally manufactured drugs due to the simpler and decentralized production process, the tailored composition and active pharmaceutical ingredient (API) release profile, and the personalized therapeutic capability. As 3D printing, or additive manufacturing, technologies continue developing rapidly, the 3D-printed drug market is anticipated to grow by 6% annually and to exceed $400 million USD by 2025. Although a comprehensive regulatory and legal framework is yet to be established, a number of globally recognized pharmaceutical companies, such as GlaxoSmithKline and Aprecia Pharmaceuticals, have already positioned themselves as innovators in the field. In this article, we provide a brief overview of technological innovations and current challenges in the 3D-printed drug industry.
3D-printed drug formulation technologies:
In general, 3D-printed objects are obtained through binding/adhesion and thermal or photochemical transformation of powdered, liquid, molten, or softened materials. Unsurprisingly, as illustrated in Figure 1, 3D-printing pharmaceutical technologies are based upon these processes.
Among the established, though not yet fully commercialized, 3D-printed drug formulation techniques, drop-on-solid deposition (DOS), also known as inkjet-powder bed process, and fused deposition modeling (FDM) are the most widely used methods.
Drop-on-solid deposition (DOS)
In DOS, the powdered material is solidified in successive layers by spraying a liquid binder; here, the API can be dispersed either in the liquid or solid phases. In particular, discharging excipient-rich binder onto API-loaded powder (the print glue approach) offers reduced formulation complexity, since similar binders are compatible with a broad range of API powders, higher API content, and better output, since multiple inkjet heads can work in parallel.
Though the print glue approach has been successfully employed in the production of Spritam, the first US FDA–approved 3D-printed drug, this method impedes the production of tailored-dose medicines because of the need to precisely arrange varying API content powder.
Fused deposition modeling (FDM)
FDM, on the other hand, entails extruding and cooling molten material and is by far the most extensively researched production method due to its relative simplicity. Here, filaments made of thermoplastic polymers are either soaked in API solutions and then extruded or, more often, melted and mixed with APIs, cooled, and re-extruded into a desired shape, usually a tablet.
The major drawbacks of FDM are low output, small and difficult-to-tailor drug dose, and inadequate dissolution profile (especially for API-soaked filaments), as well as the necessity for the right filament mechanical properties for smooth manufacture and the risk of compromising API properties (e.g., recrystallization during filament storage, partial decomposition due to multiple heating stages).
A brief overview of other 3D-printing drug technologies and several examples of drug formulations are given in Tables 1 and 2, respectively.
Table 1. Working principle and pros and cons of 3D-printing drug technologies
Table 2. Examples* of 3D-printed drugs
In summary, in spite of the existence of several 3D-printing drug formulation technologies, out of which drop-on-solid deposition and fused deposition modeling are at the forefront, the technological complexity, inadequate drug formulation flexibility, and output limit widespread application in the pharmaceutical industry.
Legal and regulatory framework for 3D-printed drugs:
Besides the technological challenges, 3D-printed medicines must also comply with stringent pharmaceutical standards. Specifically, manufactured 3D-printed drugs should not only meet current regulations concerning product design, manufacturing, and quality testing, but also, the 3D-printing technique used in their manufacture must conform to the corresponding standards. In 2016, the FDA issued a technical guide for 3D-printed medical devices which, in addition to various considerations and recommendations, indicates that each 3D-printing technique will require a separate set of rules in the future. As for 3D-printed drugs, the FDA’s thinking is currently being shaped and is yet to be publicized in a similar manner.
Among the principal challenges facing regulators are the difficulties of ensuring accountability, good drug quality, and safe use. Since safe drug administration requires solid knowledge of pharmaceutical sciences and the patient’s medical history, it is unclear at present how the right to produce medication will be conferred on healthcare professionals versus pharmacists. Furthermore, healthcare specialists will have to undergo thorough training in using various 3D-printed drug formulation technologies, somehow learn to recognize quality defects, and assess possible adverse effects in just-made, and sometimes advanced formulation, medications.
In summary, as no regulations specifically govern 3D-printed technology and medicines at present, a well-defined legal and regulatory framework will prove necessary for successful implementation and safe use of such techniques and medicines.
Future outlook and closing remarks:
Technological and regulatory challenges notwithstanding, 3D-printed medicines are bound to transform the pharmaceutical industry. Although it is unlikely that 3D printing will completely replace conventional production processes, its advantages – flexible dosing, innovative API delivery concepts, and decentralized manufacturing, to name but a few – will continue to entice drug manufacturers into exploring and adopting the technology. The trend will likely be further accelerated by the rapid development of personalized medications, which in 2019 accounted for more than 1 in 4 FDA-approved drugs, and which are expected to continue increasing in importance.
